Electrochemical reactions are chemical reactions in which electrons are transferred from one atom to another. Electrochemistry is thus a branch of chemistry that deals with the chemical changes produced by electricity and conversely, the production of electricity by chemical changes. A basic overview of electrochemistry may be obtained, for example, from Stoner et al. Bioelectrochemistry and Bioengineering, 9, (1982) 229-243.
Three types of electrochemical reactions may be distinguished, as follows:
i. An oxidation reaction, in which electrons are lost by atoms of the species involved in the reaction, so that the atoms become more positive, i.e., their oxidation state increases. In an oxidation reaction, electrons appear as products.
ii. A reduction reaction, in which electrons are gained by the species involved in the reaction, so that they become less positive, i.e., their oxidation state decreases. In a reduction reaction, electrons appear as reactants.
iii. A redox reaction, which involves both a reduction and an oxidation, and is called redox as an abbreviation to these. The stoichiometry of a redox reaction is such that all the electrons lost in the oxidation are gained in the reduction, so in a redox reaction, electrons do not appear explicitly.
One may thus define a reducing agent, as a species that reduces another species, and is itself oxidized in the process. Similarly, one may define an oxidizing agent, as a species that oxidizes another species, and is itself reduced in the process.
Two types of electrical conductors are operative in electrochemical reactions. An electronic conductor, such as a metal, and an ionic conductor, such as a solution containing ions, often called an electrolyte solution, or an electrolyte.
An electronic conductor, such as a metal, in contact with an electrolyte, is termed, an electrode. An electrode on whose surface an oxidation reaction takes place is defined as an anode. The anode acts as an electron sink to the electrolyte. Similarly, an electrode on whose surface a reduction reaction takes place is a cathode. The cathode acts as an electron source to the electrolyte.
In corrosion reactions, an electrochemical reaction may be sustained by a single metal, immersed in an electrolyte. The corroding metal acts both as the anode and the cathode. For example, when a strip of zinc is immersed in an acidic solution, an oxidation reaction takes place on its surface, as follows:Zn→Zn2++2e−  [I]
This process cannot continue for any significant length of time, without a suitable cathodic process, in which the electrons are consumed. Thus the strip of metal zinc also acts as a cathode, providing a nucleation site and a source for the electrons, for example, in the cathodic reaction:2H++2e−→H2  [II]
Corrosion reactions may also take place in a neutral environment, wherein the cathodic reaction may cause the solution to become more alkaline:O2+2H2O+4e−→4(OH)−  [III]
Although the zinc strip may act both as anode and as cathode, the addition of a second conducting strip, connected by wire to the zinc strip, will form an electrode pair. If the second strip is less active than the zinc, then the zinc strip will operate as the anode, and the second strip will operate as the cathode.
Certain metals such as platinum, though inert to electrochemical reactions, have a catalytic effect on the corrosion reaction. For example, when using platinum as a cathode, for reaction [II], the rate of the reaction may increase by a factor of 104-105, compared to its rate on zinc
Two or more electrodes, immersed in an electrolyte and connected by an electronic conductor, form an electrochemical cell.
In a galvanic electrochemical cell, current flows, power is produced, and the cell reaction proceeds spontaneously.
In an electrolytic electrochemical cell, current flows, power is consumed, and the cell reaction, which is driven, is the reverse of the spontaneous reaction of the glavanic cell.
In a reversible electrochemical cell, an infinitesimal change in cell potential can cause the reaction to proceed in either direction.
Chemists have selected the electrode reaction of hydrogen, under standard conditions of pressure and concentration, as a basis against which others electrode reactions are compared, and have termed it, standard hydrogen electrode (S.H.E.). The physically measured potential difference across a reversible cell made up of any electrode and a standard hydrogen electrode is called the reversible potential of the electrode, E. If the electrode (other than hydrogen) is also being operated under standard conditions of pressure and concentrations, the potential difference across the cell is the standard electrode potential, E0 of the electrode other than hydrogen.
The Nernst Equation for an electrode links the actual (measurable) reversible potential of an electrode E, to the standard reversible potential, E0. It may be described as:E=E0−(0.05915/n)log(activity of the reactants/activity of the products),
where n is the reaction charge (the number of electrons that are transferred).
Another use of the Nermst equation is to provide the activity ratio, which is approximately equal to the concentration ratio between the reactants and products. Given the reversible potential at an electrode E, and the concentration of the reactants, the concentration of the products may be calculated, and vise versa.
While electrochemistry is extensively applied in many technological fields, its application in vivo is limited to fewer reports and applications.
Electrochemical treatment of tumors is referred to in the medical literature as ECT.
In an ECT procedure, electrodes are implanted at spaced positions in or around the malignant tumor to be treated. Applied across these electrodes is a low DC voltage usually having a magnitude of less than 10 volts, causing a current to flow between the electrodes through the tumor. Due to an electrochemical process, reaction products are formed, which include cytotoxic agents that act to destroy the tumor cells.
In the ECT technique disclosed by Li et al., in Bioelectromagnetic 18:2-7 (1997), in the article “Effects of Direct Current on Dog Liver: Possible Mechanisms For Tumor Electrochemical Treatment” two platinum anode and cathode electrodes were inserted in a dog's liver with a 3 cm separation therebetween. Applied across these electrodes was a DC voltage of 8.5 volts, giving rise to an average current through the liver of 30 mA. This was continued for 69 minutes, with a total charge of 124 coulombs.
The concentration of selected ions near the anode and cathode were measured. The concentration of Na+ and K+ ions were found to be higher around the cathode, whereas the concentration of Cl− ions was higher around the anode. Water content and pH were determined near the anode and cathode, the pH values being 2.1 near the anode and 12.9 near the cathode. The released gases were identified as chlorine at the anode and hydrogen at the cathode. The series of electrochemical reactions which took place during ECT resulted in the rapid and complete destruction of both normal and tumor cells in the liver.
Another example of ECT appears in the article “Electrochemical Treatment of Lung Cancer” by Xin et al. in Bioelectromagnetics 18:8-13 (1997). In this ECT procedure platinum electrodes were inserted transcutaneously into a tumor, the voltage applied thereto was in the 6-8 volt range, the current was in the 40 to 100 mA range, and the electric charge, 100 coulombs per cm of tumor diameter.
According to this article, the clinical results indicate that ECT provides a simple, safe and effective way of treating lung cancers that are surgically inoperable and are not responsive to chemotherapy or radiotherapy.
Also disclosing ECT techniques are Chou et al., Bioelectromagnetics 18:14-24 (1997); Yen et al., Bioelectromagnetics 20:34-41 (1999); Turler at al., Bioelectromagnetics 21:395-401 (2000); Ren at al., Bioelectromagnetics 22:205-211 (2001); U.S. Pat. No. 5,360,440 to Andersen and U.S. Pat. No. 6,021,347 to Herbst et al.
Electrochemical reactions as a function of pH and electrode potential can be predicted by means of a Pourbaix diagram, as disclosed in the Atlas of Electrochemical Equilibria in Aqueous Solutions—Pergamon Press, 1986—by Pourbaix.
While U.S. Pat. No. 5,458,627 to Baranowski Jr., et al. does not relate to ECT but to the electrochemically controlled stimulation of osteogenesis, it is nevertheless of prior art interest, for it discloses that reaction products produced by an electrochemical reaction includes not only hydrogen and oxygen, but also hydrogen peroxide.
In the text Methods in Cell Biology, Vol. 46—Cell Death—published by Academic Press, it is noted (on page 163), that hydrogen peroxide has been reported to be an inducer of cell death in various cell systems. This type of cell death is attributed to the direct cytotoxicity of H2O2 and other oxidant species generated from H2O2.
The above described ECT technologies are limited in several aspects. First, they all pertain to the treatment of solid tumor masses, yet other applications are not envisaged. Second, they all fail to teach implantable electrochemical devices which are controlled and/or powered via telemetry.
U.S. Pat. Nos. 5,797,898 and 6,123,861 to Santini Jr. et al. both describe microchips which comprise a plurality of drug containing capped reservoirs, whereas in one embodiment the release of the drug therefrom is effected by disintegration of the caps via an electrochemical reaction.
While Santini Jr. et al. teach an electrochemical in vivo drug release mechanism effected by telemetry, Santini Jr. et al. fails to teach the in vivo electrochemical production of therapeutic agents.
U.S. Pat. No. 6,185,455, teaches functional neuromuscular stimulation (FNS) or functional electrical stimulation (FES) devices, designed also to locally release drugs that inhibit physiological reactions against the devices.
U.S. Pat. No. 5,938,903 teaches a microelectrode for inserting in vivo, in vitro into a warm-blooded or cold blooded animal brain or body, or extra-corporeally and measuring intracellular and/or extracellular concentration and/or release and/or reuptake of one or more biogenic chemicals while measuring said chemical in vivo or in vitro.
U.S. Pat. No. 5,833,715 teaches a pacing lead having a stylet introduced anti-inflammatory drug delivery element advanceable from the distal tip electrode. The element is formed as a moldable biocompatible composite material. The element has a biocompatible matrix material which may be combined with drugs and therapeutic agents to deliver the drugs and agents by co-dissolution or diffusion to the point of either passive or active fixation. The drug delivery element may be rigid and serve to center an active fixation mechanism, preferably a helix, which penetrates the myocardium.
U.S. Pat. No. 3,868,578 teaches a method and apparatus for electroanalysis.
U.S. Pat. No. 6,201,991 teaches a method and system for preventing or treating atherosclerosis in which a blood vessel susceptible to or containing atherosclerotic plaque is subjected to a low-frequency electrical impulse at an effective rate and amplitude to prevent or impede the establishment or decrease the size of the plaque in the vessel. The system can be implanted into the body of a patient or applied externally to the skin.
U.S. Pat. No. 5,360,440 teaches an apparatus for the in situ generation of an electrical current in a biological environment characterized by including an electrolytic fluid. The apparatus comprises first and second electrodes of differing electrochemical potentials separated by an insulator. The apparatus is adapted to be implanted in the environment. The presence of the electrolytic fluid and formation of a current path by hyperplastic cells bridging the electrodes enables electrolysis to occur and a direct current to pass through the current path to impede hyperplastic cell growth.
U.S. Pat. No. 6,206,914 teaches an implantable system that includes a carrier and eukaryotic cells, which produce and release a therapeutic agent, and a stimulating element for stimulating the release of the therapeutic agent. The system can also include a sensing element for monitoring a physiological condition and triggering the stimulating element to stimulate the delivery device to release the therapeutic agent. Alternatively, the patient in whom the system is implanted can activate the stimulating element to release the therapeutic agent. In one embodiment the carrier is medical electrical electrodes.
U.S. Pat. No. 6,366,808 describes an implantable electrical method and apparatus for the treatment of cancer tumors based on the usage of various levels of electrical fields and current to assist in specific ways to reduce tumor size. The method comprises: (1) implanting at least one electrode into or near a tumor, (2) implanting a source of electrical power, (3) connecting the electrode to the source of electrical power and (4) delivering electrical current into the tumor. Alternatively, the method comprises: (1) implanting at least one electrode into a tumor, (2) implanting a source of electrical power, (3) connecting the electrode to the source of electrical power, (4) monitoring at least one voltage from within tissue, and (5) delivering electrical current into the tumor. In both cases, it is the electrical current that provides the therapeutic action.
U.S. Pat. No. 5,951,458 describes a method for inhibiting restenosis by local application of an oxidizing agent to blood vessel walls. Preferred oxidizing agents include peroxides, most preferably hydrogen peroxide. Oxidizing agents can be delivered utilizing drug delivery balloon catheters. Preferred delivery catheters include an inflatable balloon having a perfusion lumen therethrough to allow for longer application periods. Oxidizing agents can be delivered either alone or in conjunction with radiation or stent delivery. One method includes local delivery of 0.1% hydrogen peroxide to a dilated stenosis wall for a period of 10 minutes at a rate of 0.5 cc per minute.
Each one of these patents, however, fails to teach in vivo electrochemical production of therapeutic agents.
There is thus a great need for and it would be highly advantageous to have methods, systems and devices for in vivo electrochemical production of therapeutic agents.